Background. The granulomatous reaction pattern is characterized by the presence of
granulomata, i.e. collections of histiocytes or epithelioid histiocytes, in the dermis, with or
without admixed multinucleated giant cells and other types of inflammatory cells. The
granulomata can show peculiar arrangements, accessory features such as necrosis,
suppuration, or necrobiosis, and the presence of organisms or foreign material. Based on the
histological features, granulomata can be sub-classified in the following types: sarcoidal, with
the classic “naked” appearance; tuberculoid, characterized by central “caseation” necrosis;
necrobiotic, showing more loose arrangement and necrobiosis (collagenolysis); suppurative,
featuring central collections of neutrophils; foreign body-type, in which foreign material,
either exogenous or endogenous, is identifiable; xanthogranulomatous, characterized by
histiocytes with foamy or pale cytoplasm and admixture of other inflammatory cells; a
miscellanea of other conditions.1
Case report N#1. A 28-years old woman, born in Philippines, presented a solitary, annular
plaque on the lower leg, asymptomatic and slowly enlarging in the last few months. A 4-mm
punch biopsy was performed on the border of the lesion and sent for histological examination
with a clinical diagnosis of granuloma annulare. The haematoxylin-eosin stained slide
showed a granulomatous inflammatory infiltrate in the superficial and deep dermis, coupled
to a moderate lymphocytic component admixed with few plasma cells. The granulomata were
arranged mostly around vessels and encased a nerve, as highlighted by immunostaining for S100 protein. Special stains (PAS, Grocott, Ziehl-Neelsen, Fite) failed to show
microorganisms. PCR studies were not performed. A diagnosis suspicious for leprosy,
tuberculoid type, was rendered. The patient was referred to a national centre for infectious
diseases (Genoa) for further investigations. The diagnosis of leprosy, tuberculoid type, was
The presence of granulomata should always suggest to look for an infectious agent. It is also
recommended to perform special stains on multiple sections. Despite exhaustive search, these
stains can fail to demonstrate the presence of microorganisms. The presence of perineural
granulomatous inflammation in this case strongly addressed toward the diagnosis of leprosy.
Case report N#2. A 55–years old woman, living in Sicily, complained of erythematous
plaques on face and trunk for 2 years. Histological examination of a punch biopsy from the
dorsum showed a granulomatous inflammatory infiltrate throughout the dermis, around
vessels and also surrounding nerves. Special stains were negative. The pattern of distribution
suggested an infectious disease, i.e. leprosy, but this possibility was excluded by further
investigations. The clinical history of the patient allowed to achieve the right diagnosis: the
woman suffered from hypogammaglobulinemia and biliary cirrhosis and had had a diagnosis
common variable immunodeficiency. Patients with immunodeficiency disorders can
develop cutaneous lesions with a granulomatous reaction pattern.
Moreover, a patient with
congenital combined immunodeficiency has been reported , whose cutaneous lesions featured
granulomata with perineural distribution, 3 analogously to the present case.
Besides the two stereotypical cutaneous granulomatous diseases, i.e. granuloma annulare and
necrobiosis lipoidica, the granulomatous reaction pattern in the skin can have several causes
and associations. It can be due to the deposition of foreign material, or to prolonged sun-light
exposure leading to actinic changes, such as the group of so-called elastolytic granulomata. It
can be observed in a large number of infectious diseases (TBC and non tuberculous
mycobacteriosis, leprosy, leishmaniasis, fungal infections). It can be related to systemic
conditions, such as sarcoidosis, Crohn’s disease, Rosai-Dorfman disease, haematological
disorders, immunologic disorders, and also to the use of certain drugs. On the other hand, it
is known also that a skin disease characterized by a peculiar granulomatous pattern at
histology, such as granuloma annulare, can show protean clinical manifestations.4
Infrequently, mycosis fungoides features a granulomatous pattern that overlaps the
histological characters of granuloma annulare. Only few subtle clues allow to make the
differential diagnosis between the two diseases, and sometimes the differentiation is almost
impossible and can only rely on molecular biology.5 Moreover, granuloma annulare-like
features can be observed in certain drug reactions, again with only subtle histological
differences.6 Finally, pathologists should be aware of the possibility that an apparently
innocent granulomatous reaction can hide a life-threatening condition, such as lymphoma. 7
All these observations underline the importance of the clinico-pathological correlations when
one is dealing with a granulomatous reaction in the skin, since histology alone could not be
sufficient and sometimes can also lead toward the wrong diagnosis.
1. Weedon D. Skin Pathology. 3rd Ed.
2. Mitra A, Pollock B, Gooi J, et al. Cutaneous granulomas associated with primary
immunodeficiency disorders. Br J Dermatol 2005; 153: 194-199.
3. Krupnick AI, Shim H, Phelps RG, et al. Cutaneous granulomas masquerading as
tuberculoid leprosy in a patient with congenital combined immunodeficiency. Mt Sinai
J Med 2001; 68: 326-330.
4. McKee PH, Calonje E, Granter SR. Pathology of the skin with clinical correlations.
Vol. 1. 3rd Ed.
5. Su LD, Kim YH, LeBoit PE, et al. Interstitial mycosis fungoides, a variant of mycosis
fungoides resembling granuloma annulare and inflammatory morphea. J Cutan Pathol
2002; 29: 135-141.
6. Magro CM, Crowson AN, Shapiro BL. The interstitial granulomatous drug reaction: a
distinctive clinical and pathological entity. J Cutan Pathol 1998; 25: 72-78.
7. Scarabello A, Leinweber B, Ardigò M, et al. Cutaneous lymphomas with prominent
granulomatous reaction: a potential pitfall in the histopathologic diagnosis of cutaneous
T- and B-cell lymphomas. Am J Surg Pathol 2002; 26: 1259-1268.